Individualized treatment decision-making is one of the most important challenges of medicine. To this end, a number of studies have recently appeared that associate clinical variables or gene-expression profile with disease outcome, thereby providing help for clinicians in treatment decisions in several diseases (e.g. Hodgkin disease, lymphoma).
Disease activity in rheumatoid arthritis (RA) leads to progressive joint and cartilage destruction. (1) Patients with active RA generally experience declining functionality and disability within two years of disease onset. (2) RA treatment is, since the last decennium, characterized by earlier and more intensive treatment with disease-modifying antirheumatic drugs (DMARDs), as this treatment strategy prevents joint damage and functional disability. Recent clinical studies demonstrate that early therapeutic intervention with combination strategies, with or without anti-tumor necrosis factor agents (anti-TNF agents) are superior to monotherapy with DMARDs and considerably improves RA prognosis. (3-5)
Although combination strategies are more efficacious, such intensive approach is probably not necessary for all newly diagnosed RA patients. (6; 7) In addition, combination treatment with anti-TNF agents or corticosteroids possibly introduces patients to other risks, such as serious infections or osteoporosis. (8; 9) As a result, it is important to determine whether patients have a high probability of response to monotherapy to preclude or prescribe combination treatment.
Methotrexate (MTX) is the most widely used DMARD in clinical practice, although the factors determining MTX efficacy are largely unknown. The influences of demographic, clinical immunological and genetic factors on the state of disease in RA patients have been previously studied (10-18). Polymorphisms in genes encoding methylene tetrahydrofolate reductase (MTHFR), adenosine monophosphate deaminase (AMPD1), aminoimidazole carboxamide ribonucleotide transformylase (ATIC) and inosine triphosphate pyrophosphatase (ITPA) demonstrate an association with MTX response. (19-21) Non-genetic factors such as low disease activity at baseline, male sex, non-steroidal anti-inflammatory drug (NSAID) use and lower creatinine clearance are also related to MTX efficacy (22). However, these associations, alone or in combination, were not transformed into clinical decision tools to guide MTX treatment in patients.
Therefore, there is still a need to explore additional polymorphisms in genes that are associated with MTX response and a need for a clinical pharmacogenetic model that reliably predicts the efficacy of MTX monotherapy in patients with recent-onset arthritis.